This is the third of our Forum journal discussions, in which the editors of Schizophrenia Bulletin or Schizophrenia Research choose a thought-provoking recent article and provide access to the full text. A short introduction by a journal editor, below, will get us started, and then it's up to our readers to share their ideas and insights, questions and reactions to the selected paper. So read on…

by Lynn DeLisi, New York University, and Editor, Schizophrenia Research

For more than a decade, spurred by the hypothesis of schizophrenia as a neurodevelopmental disorder, researchers have looked for associations between the brain-derived neurotrophic factor (BDNF) and schizophrenia. The Val66Met polymorphism has received the most attention recently, but results have been mixed, with some finding an association between the Val allele and schizophrenia or schizophrenia spectrum disorders (e.g., Neves-Pereira et al., 2005; Rosa et al., 2006) and others finding no association (e.g., Chen et al., 2006; Jonsson et al., 2006; Watanabe et al., 2006). The finding by Egan and colleagues of Val66Met-related differences in cognitive performance in normal subjects (Egan et al., 2003) has also led to a boom in studies of this polymorphism in normal cognition and behavior, with the implication of relevance to schizophrenia.

But is it now time to throw in the towel? In their paper in press at Schizophrenia Research, Tsukasa Sasaki and colleagues at the University of Tokyo describe a study of 401 patients with schizophrenia and 569 controls that failed to find an association of Val66Met with the disorder. Furthermore, there was no association of the polymorphism with personality traits in the control group.

Some questions for discussion: Are the study populations sufficient to draw firm conclusions in this or earlier studies? Can population differences be used to explain the discrepancies? Any other methodological concerns? Any other data that we should consider? And, as always, where should we go from here?

I think schizophrenia spectrum is related to connectivity...
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I think schizophrenia spectrum is related to connectivity and plasticity changes in the millisecond range (see further discussion), while BDNF is functional for slower plasticity changes, taking days and weeks: that is why there is no correlation with schizophrenia spectrum but rather with mood disorder.

In the group of disorders we call “schizophrenia,” there may never be any gene(s) of major effects. Among its genetic causative factors, there are likely multiple susceptibility genes (locus heterogeneity) in which individuals with schizophrenia may have different combinations of genes (or haplotypes; genetic heterogeneity). For a given susceptibility gene, there is probably allelic heterogeneity as well. And to complicate things even more, we still do not quite understand the functions of most of these genes, how these susceptibility genes interact with one another and with non-genetic (or environmental) factors to bring about the signs and symptoms of schizophrenia.

So, with the genetics of schizophrenia being so complex, one should not be surprised that allelic and genotype frequencies for a particular candidate gene did not differ significantly between schizophrenia patients and healthy volunteers (Tochigi et al., 2006). While such studies may add to the “BDNF’s star” fading a little, case-control genetic association studies on complex genetic disorders alone should not cause the “star” to implode and die. After all, the major reason for BDNF’s fading star is most probably because it has had its 1 minute of fame, and the world has moved on in search of the next “superstar” in schizophrenia genetics. For its role in neurodevelopment and ongoing neuroplasticity (Gorski et al., 2003), BDNF remains a viable candidate gene that may explain certain aspects of schizophrenia (e.g., cognition and brain volume deficits) within subgroups of patients (Ho et al., 2006).

On the question of where we should go from here, a variant of the classic case-control genetic association studies has been in vogue in schizophrenia research for the past few years. Instead of testing for differences in genotype and allelic frequencies between patients and healthy volunteers, one way to tackle the genetic complexity and phenotypic heterogeneity of schizophrenia has been to study the relationships between candidate genes and endophenotypes (broadly defined as cognitive deficits on standardized neuropsychological tests, MRI brain volumes, and fMRI BOLD signal). Of course, this current rising star of genotype-endophenotype genetic association studies will inevitably become a future fading star when research methods advance and because we constantly need a new superstar. Hopefully, it will be more of the former and less of the latter.

To my mind, at the molecular level schizophrenia might be...
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To my mind, at the molecular level schizophrenia might be divided into different diseases with different molecular pathology. Something surprising for me is the fact that permanent polymorphisms in DNA might cause schizophrenia, which is not always a permanent disease. So I do believe in environmental factors that change the transcriptome and proteome of cells periodically, not permanently.

References:

Harrison and Weinberger. Schizophrenia genes, gene expression, and neuropathology: on the matter of their convergence Molecular Psychiatry. 2005;10:40–6. Abstract